Nrf2激动剂Dh404预防糖尿病心肌胰岛素抵抗和糖尿病心肌病的机制

氧化应激是导致糖尿病心肌胰岛素抵抗和糖尿病心肌病的关键因素。核因子E2相关因子2 (Nrf2)在机体氧化－还原体系调控中起着重要的作用。预实验发现：晚期糖尿病病人和实验动物心肌Nrf2表达显著下调、心肌损伤加重；利用Nrf2激活剂Dh404诱导Nrf2上调能有效预防糖尿病动物心肌氧化损伤、保护心肌胰岛素信号。课题组据此提出科学假设：Nrf2是预防糖尿病心肌胰岛素抵抗和糖尿病心肌病的有效靶点，采用Nrf2激动剂Dh404上调Nrf2的功能、增强其下游多种抗氧化信号能有效预防心肌氧化损伤和胰岛素抵抗，从而预防糖尿病心肌病。本课题的主要目标是考察以Nrf2为靶点、利用Nrf2激动剂Dh404预防糖尿病心肌胰岛素抵抗和心肌病的可行性和有效性，同时以多种转基因动物模型为研究手段，解析Dh404上调Nrf2预防糖尿病心肌胰岛素抵抗和心肌病的分子机制，为临床以Nrf2为靶点预防糖尿病心肌病提供科学依据。

Diabetic cardiomyopathy is one of major diabetic complications. Oxidative stress is the predominant pathogenesis of diabetic cardiac insulin resistance and diabetic cardiomyopathy. The nuclear factor- erythroid 2-related factor (Nrf2) is a transcription factor that plays a crucial role in the cellular redox homeostasis through up-regulation of several antioxidants and detoxifying enzymes. In our preliminary studies, we have found that the expression and function of Nrf2 (nuclear translocation) were significantly down-regulated in cardiac tissue in late-stage diabetic patients and experimental animals, which was accompanies by serious cardiac oxidative damage; while a novel Nrf2 activator Dh404 can up-regulate the function of Nrf2 and its downstream antioxidant genes to prevent cardiac oxidative damage and protect cardiac insulin signaling in a diabetic animal model. Based on these findings, we hypothesize that Nrf2 is a potential therapeutic target for the prevention of diabetic cardiac insulin resistance and diabetic cardiomyopathy. Utilization of Nrf2 activator Dh404 up-regulation of the function of Nrf2 and its downstream multiple antioxidants can protect the heart from diabetic oxidative damage, cardiac insulin resistance and consequently prevent diabetic cardiomyopathy. To test our hypothesis, three specific aims are proposed: 1) To define whether Nrf2 activator Dh404 can prevent diabetic cardiac insulin resistance and diabetic cardiomyopathy in streptozotocin-induced and spontaneous OVE26 type 1 diabetes; 2) To define the pivotal role of Nrf2 in Nrf2 activator Dh404 protection of heart from diabetes; 3) To define the mechanism that Dh404 up-regulation of Nrf2 to prevent cardiac insulin resistance and cardiomyopathy in diabetes. The objective of this project is to verify that targeting to up-regulation of Nrf2 function in vivo by its activator Dh404 can provide a significant protection from diabetes-induced cardiac oxidative damage, insulin resistance, remodeling and dysfunction, which will provide strong scientific evidences for targeting Nrf2 to prevent diabetic complication in clinics.